Elsevier

Biological Psychiatry

Volume 50, Issue 10, 15 November 2001, Pages 775-782
Biological Psychiatry

Fluoxetine and norfluoxetine concentrations in nursing infants and breast milk

https://doi.org/10.1016/S0006-3223(01)01197-0Get rights and content

Abstract

Background: This study’s goal was to characterize nursing infants’ exposure to fluoxetine through breast milk and to identify variables for minimizing such exposure.

Methods: Nursing women on stable daily doses of fluoxetine were recruited into the study. Breast milk, maternal and infant serum concentrations of fluoxetine and norfluoxetine were determined with high-performance liquid chromatography.

Results: Nineteen nursing women one with a pair of dizygotic twins participated in the study. The women were on stable daily doses of fluoxetine (10–60 mg/day) and all but two took the medication during the last trimester of pregnancy. Fluoxetine was detectable in 30% (n = 6) of the nursing infant sera (< 1–84 ng/mL), whereas norfluoxetine was found in 85% (N = 17) (< 1–265 ng/mL). Peak breast milk concentrations occurred approximately 8 hours after maternal dosing and predicted norfluoxetine concentrations in infant serum. Maternal serum fluoxetine and norfluoxetine concentrations correlated highly with infant norfluoxetine concentrations. A daily maternal fluoxetine dosage of 20 mg or lower was significantly less likely to produce detectable concentrations of either fluoxetine or norfluoxetine in infants compared to higher daily dosages. No adverse effects were reported in any infant.

Conclusions: Our findings demonstrate that maternal serum and peak breast milk concentrations of fluoxetine and norfluoxetine predict nursing infant serum norfluoxetine concentrations. In nursing women taking 20 mg/day or less of fluoxetine, infant serum concentrations were typically low.

Introduction

For many women, the postpartum period represents a time of increased vulnerability to psychiatric disorders. Women with a history of major depression are particularly at risk for depression following delivery (O’Hara 1995). Postpartum illnesses are not limited to depression but also include anxiety disorders and worsening of pre-existing conditions such as eating disorders Shear and Mammen 1995, Sichel et al 1993, Stein and Fairburn 1996. New mothers with mood and anxiety disorders may benefit from treatment with antidepressant medications such as the selective serotonin uptake inhibitors (SSRIs), as was shown in a recent study of fluoxetine for the treatment of postpartum depression (Appleby et al 1997). However, the decision to use antidepressants in the postpartum period is often complicated by a desire to breast-feed and concern about exposing the infant to medication. Therefore, studies that expand the information on the safety, risks and benefits of antidepressant medication use during nursing are of potential importance in the care of many new mothers.

The data regarding the use of fluoxetine during breast-feeding have generated conflicting recommendations that warrant further investigation. Several years ago, a case report described a breast-fed infant who developed colic and sleep disturbance purportedly in association with maternal use of fluoxetine 20 mg/day (Lester et al 1993). The infant’s serum concentrations of fluoxetine and norfluoxetine were 340 ng/mL and 208 ng/mL, respectively. This case report prompted a revision in the labeling for fluoxetine to recommend against its use in breast-feeding women. A second case suggestive of adverse effects involved a nursing infant’s mother treated with fluoxetine 20 mg/day, carbamazepine 600 mg/day and buspirone 45 mg/day, the mother reported a 60 to 90-sec episode during which the infant’s “eyes rolled back, upper limbs streched out and she became limp” (Brent and Wisner 1998). The infant’s serum concentrations of fluoxetine and norfluoxetine were 61 ng/mL and 57 ng/mL, respectively, at the time of this event. Subsequent neurologic evaluation and electroencephalography were normal and the episode did not recur. Kristensen and colleagues (1999) noted crying, irritability and poor feeding in two of the 14 nursing infants (Kristensen et al 1999), and found detectable concentrations of fluoxetine and norfluoxetine concentrations in 5/9 and 7/9 nursing infants, respectively, at ranges of 20–252 ng/mL and 17–187 ng/mL. Finally, a recent retrospective study that compared 26 nursing infants whose mothers took fluoxetine with 38 nursing infants whose mothers did not take the medication found a significantly lower growth rate based on pediatric records among the fluoxetine-exposed group over the first 6 months of age (Chambers et al 1999); however, no measure of medication exposure (infant sera or breast milk) was obtained.

In contrast, several reports have failed to observe such purported adverse effects of fluoxetine exposure in nursing infants. Two separate case reports observed no adverse effects of fluoxetine exposure in two nursing infants Burch and Wells 1992, Isenberg 1990 but did not obtain infant serum concentrations of the medication. Two case series involving serum sampling in a total of five infants found no detectable concentrations of fluoxetine or norfluoxetine in the infants’ serum Taddio et al 1996, Yoshida et al 1997. In a study that included 14 nursing infants whose mothers were treated with fluoxetine (Birnbaum et al 1999), eight infants had detectable fluoxetine and/or norfluoxetine in their serum, at 28–82 ng/mL and 21–250 ng/mL, respectively. This study utilized commercial laboratories with a higher limit of detection (20–50 ng/mL) and, therefore, concentrations below these limits would not have been detected. These three studies reported no adverse effects in the infants, as assessed by the mother Birnbaum et al 1999, Taddio et al 1996 or at 12 months of age using the Bayley Scales of Infant Development (Yoshida et al 1998).

The goal of the present investigation was to expand the data on the relative safety of fluoxetine use during breast-feeding and to ascertain if maternal dosage and medication concentrations in breast milk and maternal serum have a predictive value for infant serum concentrations.

Section snippets

Methods and materials

Twenty infants (including one pair of dizygotic twins) from 19 breast-feeding mothers who presented to UCLA’s Pregnancy and Postpartum Mood Disorders Program or responded to newspaper advertisements were included in the study. An additional mother provided breast milk samples but no maternal or infant serum samples. Written informed consent was obtained from each subject for collection of breast milk samples and maternal and infant serum samples.

Results

The women who participated in the study were Caucasian, in good health, ranging in age from 24 to 40 years old, and on fluoxetine 10–60 mg taken once daily for treatment of major depression. All except one had been on fluoxetine during pregnancy. One woman was additionally on buspirone and another was on acyclovir. None of the infants were exposed to any other medications at the time of the study

Eighteen maternal serum samples and 20 infant serum samples were obtained from the 20 mother–infant

Discussion

This study identified variables that would allow clinicians to predict nursing infants’ serum concentrations on the basis of maternal dosage, maternal serum concentration or maternal breast milk concentration of medication. Fluoxetine and norfluoxetine were typically nondetectable or at very low concentrations (< 5 ng/mL) in the serum of the breast-fed infants if maternal medication dosage was 20 mg/day or lower, or if maternal serum concentrations of total medication (fluoxetine plus

Acknowledgements

This project was supported by Grant MH01451-01 from the National Institutes of Mental Health, Bethesda, Maryland.

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